Pancreatic cancer is the 3rd leading cause of cancer-related deaths in the United States with a 5-year survival less than 9%. Resistance to standard therapy and limited response to immune checkpoint blockade due to the immunosuppressive and stroma-rich microenvironment remain a major challenge in the treatment of this disease. A key cellular program involved in therapeutic resistance is epithelial plasticity, which is associated with invasion and metastasis, as well as tumor cell evasion of immune surveillance. The receptor tyrosine kinase Axl is a critical driver of epithelial plasticity. High expression and activity of Axl is associated with poor prognosis, metastasis, and therapy resistance in multiple types of cancer including pancreatic cancer. Here, we show that an Axl inhibitor (TP-0903), has anti-tumor and therapy sensitizing effects in pre-clinical models of pancreatic cancer. Syngeneic orthotopic models treated with TP-0903 alone or combination with gemcitabine and/or immune checkpoint blockade (anti-PD-1) reduced primary and metastatic tumor burden. Therapy with TP-0903, gemcitabine or the combinations significantly reduced primary tumor weight (p<0.05); however, anti-PD-1 alone had no effect. The incidence of micrometastasis was reduced from 62.5% in vehicle group to 14% with TP-0903, while the triple therapy (TP-0903/gemcitabine/anti-PD-1) completely eliminated micrometastasis in 9 animals. Furthermore, Nanostring analysis of the tumors demonstrated upregulated pro-inflammatory and immune activation genes in TP-0903-treated groups compared to the vehicle, indicating pharmacologic inhibition of Axl activation leads to a more immunostimulatory microenvironment. This effect was augmented when TP-0903 was combined with gemcitabine and anti-PD-1. Additionally, survival studies are being completed in genetically engineered mouse models treated with TP-0903 single agent or in combination with chemo- and immune-therapy. Consistent with the syngeneic model, preliminary evidence suggests that TP-0903 sensitizes the tumors to chemotherapy and immune checkpoint blockade, leading to a significant anti-tumor, anti-metastatic, and pro-survival effect on GEMMs of pancreatic cancer. These results support TP-0903 as a novel therapy for treatment of pancreatic cancer, a disease that is in desperate need for effective therapy.
Citation Format: Yuqing Zhang, Emily N Arner, Jason E Toombs, Jason M Foulks, Steven L Warner, Rolf A Brekken. Axl inhibitor TP-0903 augments chemo- and immunotherapy efficacy in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C092. doi:10.1158/1535-7163.TARG-19-C092